It is well known that ultrasound imaging is a valuable diagnostic tool, for example in studies of the vascular system, which term used herein embraces both vasculature and microvasculature as well as tissue penetrated thereby. Specific applications include cardiography and studies of tissue microvasculature. Such imaging is based on penetration of ultrasound waves, e.g. in the frequency range 1-10 MHz, into the subject, the waves interacting with interfaces of body tissues and fluids. Contrast in an ultrasound image derives from differential reflection and absorption of the ultrasound waves at such interfaces. Thus, for example, reflected waves may be analysed to give "grey-scale" images representing such interfaces on an appropriate visual display unit; Doppler techniques may be used to evaluate blood flow, information regarding which may, for example, be superimposed in colour upon such a grey-scale image.
It has long been recognised that contrast agents may advantageously be used to increase the difference in acoustic properties between different tissues and/or fluids, such agents typically being administered by intravenous injection when vascular studies are to be performed. Numerous contrast agent formulations have been proposed over the last 25 years, including emulsions, solid particles, water-soluble compounds, free gas bubbles and various types of encapsulated gas-containing systems; it is, however, generally accepted that low density contrast agents which are easily compressible are particularly efficient in terms of the acoustic backscatter they generate, and particular interest has therefore been shown in gas-containing and gas-generating systems.
Representative examples of such systems include gas-containing microparticulate contrast agents, for example as described in U.S. Pat. No. 4,442,843, EP-A-0122624, EP-A-0123235, DE-A-3834705, WO-A-9221382, WO-A-9300930, WO-A-9313802, WO-A-9313808 or WO-A-9313809; protein-encapsulated gas- or gas precursor-containing contrast agents such as Albunex.RTM. or as described in, for example, WO-A-9217213, WO-A-9406477 or WO-A-9501187; polymer- and other synthetic material-encapsulated gas- or gas precursor-containing contrast agents, for example as described in EP-A-0398935, EP-A-0458745, WO-A-9217212, WO-A-9317718, WO-A-9506518 or WO-A-9521631; systems employing gases selected to exhibit long term stability in vivo, for example as described in U.S. Pat. No. 5,413,774 or WO-A-9305819; and liposomal gas-containing systems, for example as described in U.S. Pat. No. 5,228,446 or U.S. Pat. No. 5,305,757. The contents of all of the foregoing documents are incorporated herein by reference.
Such contrast agents intended for administration by intravenous injection are typically designed to generate gas microbubbles having sizes in the range 1-10 .mu.m or less, e.g. 1-7 .mu.m, in order to ensure free passage through the capillary bed of the pulmonary system. Such microbubbles effectively act as point scatterers of ultrasound, and because of their random motion in fluids such as blood the backscatter which they generate will contain interference patterns due to interference between individual returning echoes. This phenomenon is termed speckle and typically produces a moving mottled effect in ultrasound images. The presence of such speckle is generally considered disadvantageous by virtue of the reduced image quality, and various techniques have been proposed for reducing speckle, for example as described in U.S. Pat. No. 5,409,007.